Activated Allogeneic Donor-derived Marrow-infiltrating Lymphocytes Display Measurable In Vitro Antitumor Activity.
Activated Allogeneic Donor-derived Marrow-infiltrating Lymphocytes Display Measurable In Vitro Antitumor Activity.
复制标题
DOI：
10.1097/cji.0000000000000256
复制
发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
当前异基因造血干细胞移植（alloHSCT）的主要限制是移植后疾病复发，表明供体来源的T细胞不足以赋予有效的抗肿瘤应答。目前复发的标准治疗方法利用供体淋巴细胞输注，其记录的疗效有限，并且还与主要与移植物抗宿主病相关的显著发病率相关。我们以前已经表明，骨髓浸润淋巴细胞（MIL）具有更广泛的抗原特异性相比，其外周血对应的自体过继性T细胞治疗设置。在这里，我们将这些观察结果扩展到检查从alloHSCT后的患者获得的MIL产生可测量的肿瘤特异性免疫的能力。我们在这里表明，从接受移植后环磷酰胺alloHSCT的患者中获得的同种异体供体来源的骨髓浸润淋巴细胞（ddMILs）可以重复扩增并用抗CD 3/CD 28珠激活。ddMIL亚群的表型表征揭示了中枢记忆表型的流行。多克隆活化的ddMIL显示出可测量的体外抗肿瘤活性。此外，来自所有患者的活化ddMIL有效地靶向第三方同种异体抗原，但对以HLA限制性方式呈递的自身抗原没有显示出反应性。总的来说，这些结果强调了激活的ddMIL的内在多克隆肿瘤特异性，并描述了一种用于产生肿瘤特异性T细胞的新方法，所述肿瘤特异性T细胞适用于alloHSCT后复发的血液恶性肿瘤的过继免疫治疗。这种方法具有显著增加肿瘤特异性和降低与当前标准供体淋巴细胞输注方法相关的毒性的潜力。
A major limitation in current allogeneic hematopoietic stem cell transplantation (alloHSCT) is disease relapse after transplant, indicating that donor-derived T cells are inadequate in imparting an effective antitumor response. The current standard treatment approach to relapse utilizes donor lymphocyte infusions that have limited documented efficacy and are also associated with significant morbidity mainly related to graft-versus-host disease. We have previously shown that marrow-infiltrating lymphocytes (MILs) have a broader antigenic specificity compared with their peripheral blood counterpart in an autologous adoptive T-cell therapy setting. Here, we extend these observations to examine the ability of MILs obtained from patients after an alloHSCT to generate measurable tumor-specific immunity. We show here that allogeneic donor-derived marrow-infiltrating lymphocytes (ddMILs) obtained from patients who underwent alloHSCT with posttransplant cyclophosphamide could be reproducibly expanded and activated with anti-CD3/CD28 beads. Phenotypic characterization of ddMILs subpopulations revealed the prevalence of a central memory phenotype. Polyclonally activated ddMILs displayed measurable in vitro antitumor activity. Furthermore, activated ddMILs from all patients effectively targeted third-party allogeneic antigens, but showed no reactivity toward self-antigens presented in an HLA-restricted manner. Collectively, these results underscore the intrinsic polyclonal tumor-specificity of activated ddMILs and describe a novel approach for the generation of tumor-specific T cells that are suitable for adoptive immunotherapy of hematological malignancies relapsed after alloHSCT. This approach has a potential to significantly increase the tumor-specificity and reduce the toxicities associated with current standard donor lymphocyte infusion approaches.